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AMSTERDAM—Long-term survival of three to 10 years was reported in nearly a quarter of patients with unresectable, metastatic, or locally advanced melanoma treated with the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-inhibiting monoclonal antibody ipilimumab, in a presentation here at the European Cancer Congress (Abstract LBA 24).

The researchers from Germany, France, and the United States conducted a pooled analysis of the longest follow-up of the largest group of patients treated with the agent, which works by reversing the inhibition of CTLA-4's natural cancer-killing mechanisms turned off by the melanoma disease process.

Principal study author Professor Dirk Schadendorf, MD, Professor and Director of the Department of Dermatology at Essen University Hospital in Germany, said in an interview that the “plateau” of overall survival beyond three years was in contrast to the past when long-term survival was the exception: “Now we have a three-year survival rate of 22 percent, and this is stable after five years, after seven years. So still more than 20 percent of patients are surviving.”

The data were pooled from 12 prospective and retrospective studies of ipilimumab treatment: two Phase III trials, eight Phase II trials, and two retrospective observational studies, for a total of 1,861 patients—two thirds of whom were previously treated. Additional data were also analyzed from an uncontrolled expanded access program with 2,985 patients.

Excluding data from the expanded-access program, the analysis showed a median survival of 11.4 months, with 254 patients living at least three years. From about three years the curve of overall survival formed a plateau, with a three-year overall survival rate of 26 percent among previously untreated patients and 20 percent in those who were previously treated—22 percent overall.

In addition, Hodi noted, there were no further deaths among patients who survived at least seven years, at which point the overall survival rate was 17 percent.

Results from the expanded-access program were consistent with the randomized study findings, he added.

Schadendorf called the therapy almost effectively curative: “We are moving to a clinical cure with a substantial fraction of patients still free of disease for more than five years,” he said.

Alexander Eggermont, MD, PhD, Director General of the Institut Gustave Roussy Comprehensive Cancer Center in Villejuif, France, said he thought long-lasting tumor control could be achieved in metastatic melanoma: “Patients apparently can keep residual tumors under control for a long time when the immune system is properly ‘reset,’ and the concept of ‘clinical cures’ becomes a reality.”

And he suggested that these survival rates could even double or triple with the addition of treatment with anti-PD1/PDL1 monoclonal antibodies: “Metastatic melanoma could become a curable disease for perhaps more than 50 percent of patients,” he predicted.

Relationship Between PFS and OS

Another study reported at the Congress looked at the relationship between progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma (Abstract 3702).

Keith Flaherty, MD, Director of the Termeer Center for Targeted Therapies at Massachusetts General Hospital, said that his group came up with definitive findings in a study that was an aggregate of all randomized trials of advanced melanoma conducted with dacarbazine (DTIC) as a control arm versus ipilimumab, dabrafenib, vemurafenib, and trametinib therapies: “What we found was a very robust relationship between PFS and OS,” he said.

The finding was highly statistically significant, he reported. Using a “correlation coefficient” between PFS and OS defined as zero for no relationship and 1.0 for a perfect relationship, the investigators observed coefficients ranging between 0.85 and 0.95.

In an interview, Flaherty said that this could accelerate future clinical research on melanoma because OS can be predicted from initial data limited to PFS: “You'd ask the question: Can we predict that with endpoints that can be achieved even within the first six months or so of a clinical trial? This data suggests, in fact, that you can: that if you observe an impact on progression-free survival in a randomized trial, it's highly likely it will translate into an overall survival benefit.”

The Long Term

One of the individual studies contributing to the pooled analysis reported by Schadendorf and Hodi found a doubling of five-year overall survival in patients randomized to have ipilimumab added to their standard dnacarbazine therapy (Abstract 3704).

Investigator Michele Maio, MD, PhD, Director of Medical Oncology & Immunotherapy at University Hospital in Siena, Italy, said that although this was a big achievement in itself, there was more to it than just a increment in overall survival: “We have confirmed that if patients make it to the third year of their disease, then the chance of dying of their melanoma decreases dramatically. So this means clearly that we have something that works in the long range for our patents.”

In addition, he said, ipilimumab's immunological mode of action was complementary to the mechanisms of the other new agents showing promise in advanced melanoma, meaning that more than one agent could be used in the same patient at different times.

“Ipilimumab has to activate the immune system, so it takes time in order to work. Other agents—like BRAF inhibitors and the MEK inhibitors—act directly at the tumor site,” he explained. So the new drugs are complementary to one another, not alternatives.

“I think we have two important ways to treat our patients,” Maio continued, “and the future will definitely be how to combine or sequence these agents in order to improve significantly the long-term survival of our metastatic melanoma patients.”

He said he was also encouraged by Flaherty's finding that PFS is a good surrogate for OS: “This will mean that we will shorten the time of our studies and observations and that we have the possibility to learn more about whether a specific agent improved the survival,” he said.

Flaherty said he was impressed by the newfound durable long-term treatment responses in patients with advanced melanoma, and he added his voice to those of others here: “Those who maintain a response beyond the second or third year of initiating treatment seem to be essentially cured of disease in terms of the absence of melanoma-related deaths thereafter. And that I think is a profound statement when you consider that complete radiographic responses happen quite infrequently.”

Cora Sternberg, MD, Chief of Medical Oncology at the San Camillo and Forlanini Hospitals in Rome, who chaired a news briefing on these melanoma data, commented: “This is the longest that we have seen patients living and I think that this is very big and important news: patients are living longer and that's what patients need to know.”

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Listen to Michele Maio and Keith Flaherty discuss more about their findings in video interviews at the Congress with Peter Goodwin.

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